The present invention provides a topical ophthalmic solution comprising an alpha-2 adrenergic receptor agonist such as brimonidine tartrate and/or pharmaceutically acceptable excipients wherein the ophthalmic solution is soluble enough to achieve therapeutic efficacy is soluble at a lower pH range of from about 5.5 to about 6.5.
The ophthalmic solution of the present invention contains from about 0.05% to about 0.2% (w/v) of brimonidine tartrate.
Brimonidine tartrate is an alpha-2-adrenergic agonist that reduces the elevated intraocular pressure (IOP) of the eye that is associated with glaucoma. The topical use of brimonidine to lower intraocular pressure in patients with glaucoma or ocular hypertension is known.
The first ophthalmic brimonidine product in the U.S. was approved by the FDA in 1996. That product, sold under the trade name Alphagan®, contained brimonidine in the form of brimonidine tartrate at a concentration of 0.2%. According to the product label, Alphagan® is adjusted (with NaOH or HCl) to a pH between 5.6 and 6.6, and further contains citric acid, polyvinyl alcohol, sodium chloride, sodium citrate, and purified water. The preservative contained in Alphagan® is benzalkonium chloride, the most widely used preservative for topical ophthalmic compositions.
In 2001, a second ophthalmic brimonidine product was approved by the U.S. FDA. This product, sold under the trade name Alphagan® P, contained brimonidine tartrate at two brimonidine concentrations, 0.15% and 0.1%, each of which is lower than the 0.2% brimonidine concentration in Alphagan®. Alphagan® P has a pH between 7.15 and 7.8, a range that is higher than that of Alphagan®. According to the product label, the lower concentration Alphagan® P formulation is sold at a pH of 7.4 to 8.0; the higher concentration is sold at a pH of 6.6 to 7.4. The preservative contained in Alphagan® P is chlorine dioxide. See U.S. Pat. Nos. 5,424,078 and 6,562,873. Alphagan® P also contains an anionic solubility enhancing component (carboxymethylcellulose) to help solubilize the brimonidine that is unionized at the pH of the compositions. Currently the innovator has discontinued marketing Alphagan®, the higher concentration, and low pH product.
Brimonidine has a pKa of 7.4. Hence, at pH below 6.6, it will be substantially ionized. For example, at a pH of 6.4, brimonidine is about 90% ionized. It is well known that ionized ophthalmic drugs have greatly reduced ocular permeability. It would have been expected that at a pH below 6.6 or 6.5, brimonidine would not permeate ocular tissue well, thereby reducing its efficacy compared to a higher pH product. It is believed that this is why the drug concentration in Alphagan® is substantially higher than in the higher-pH product Alphagan® P.
To overcome this disadvantage, the inventors of the present invention have formulated the current product with a non-ionic cellulose derivative, preferably hydroxypropyl methylcellulose (e.g., HPMC E4M grade). Without being bound by theory, it is believed that such a polymer reduces the surface tension to around 45 dynes/cm from about 72 dynes/cm, thereby helping to spread the drop more effectively around the ocular surface. Moreover, due to its viscosity, it is believed to increase retention of the drop in eye. Both of these effects are believed to help increase penetration of the drug. Surprisingly the efficacy of this invention appears to be similar to that of Alphagan® P, if not better (statistically significant), in spite of the present inventive compositions being at lower pH, wherein most of the drug is in ionized state.
The inventors of the present invention have formulated an ophthalmic solution wherein the pH of the formulation is acidic, preferably having pH from about 5.5 to about 6.5, yet is surprisingly effective compared to other low-pH products (e.g., Alphagan®). The lower pH also removes any need to use a solubility enhancing agent(s) because brimonidine is highly soluble at acidic pH (5.5-6.5) (though a solubility enhancing agent may be used if desired).
Further, the inventors of the present invention have surprisingly improved the stability of brimonidine significantly over the commercial product (Alphagan® P). The data are shown in Table 6.
Brimonidine tartrate has highly pH-dependent solubility. The solubility decreases sharply as the pH increases as shown in Table 1 (Refer U.S. Pat. No. 6,627,210 B2 page no. 13-14).
TABLE 1Solubility of brimonidine tartrate a solubilityenhancing agent over pH range of 5 to 8.Study 1Study 2pHSolubilitypHSolubility5.55≥164.45.5≥200.65.92132.65.92160.86.1430.46.0650.16.577.556.93.1972.697.41.197.451.177.770.637.830.627.860.587.880.54
The original Alphagan® included a detergent preservative, benzalkonium chloride, which was known to be somewhat irritating to the eye.
Gasset and Grant et al. showed that BAC accumulates in ocular tissue and remains there for long periods, adversely affecting both the corneal surface and the conjunctiva. Therefore, cessation of the medications may not immediately improve the condition and function of the ocular surface. These findings also suggest that corneal cell necrosis may occur in some patients who are taking multiple BAC-preserved ocular medications over long periods of time, even when the amount of BAC in any one medication is below the threshold concentration at which necrosis occurs.
It is well known in the reference literature that small organic compounds, such as benzalkonium chloride (BAC), chlorhexidine, thimerosal have excellent antimicrobial activity; however, it is now known that these small organic antimicrobials are often toxic to the sensitive tissues of the eye and can accumulate in cornea, contact lenses, particularly soft, hydrophilic contact lenses. Medications with BAC may cause disruption of the corneal surface with lower concentrations of BAC.
The preservative in Alphagan® P is stabilized chlorine dioxide (“SCD”), an oxidative preservative that was known to be compatible with the eye but Chlorine dioxide is not an ideal preservative ingredient. It is an oxidative preservative and it would oxidize brimonidine. It is difficult to stabilize and is light-sensitive as referred in U.S. Pat. No. 7,265,117.
It has been unexpectedly found that benzododecinium bromide is a quaternary ammonium compound that does not form a precipitation with brimonidine at pH of around 6.0. Benzododecinium bromide forms an ion pair with brimonidine, thereby neutralizing the charge of brimonidine. Thus it was surprising to find that benzododecinium bromide is a quaternary ammonium compound that does not form precipitation with brimonidine. In the same conditions brimonidine forms a hazy solution with benzalkonium chloride.
Hence there is an unmet medical need to prepare a topical ophthalmic solution comprising an alpha-2 adrenergic receptor agonist such as brimonidine tartrate and/or pharmaceutically acceptable excipients wherein it does not comprises a solubility enhancing agent and an oxidative preservative. Instead, when the preservative is included in the said solution, the preservative is preferably benzododecinium bromide. Benzododecinium bromide is an effective preservative for alpha-2 adrenergic receptor agonists (e.g., brimonidine) in acidic conditions.
It was surprisingly found by the inventors of the present invention that the formulation of the present invention has shown statistically significant IOP lowering efficacy when administered to normotensive and water loaded New Zealand white rabbits by ocular route. The onset of statistically significant IOP lowering efficacy was 15 minutes earlier in present invention which is same as compared to Alphagan® P, whereas both the formulations were found to be comparable at each time point observed, which indicates that the IOP lowering efficacy of both test formulations (Alphagan® P and the present invention) were statistically comparable.